Sir,
We read with great interest the recent study by Pabst et al (2009) disclosing that there is relevant prognostic heterogeneity within AML patients with CEBPA mutations and only CEBPA double mutations (CEBPAdouble-mut), but not single mutations (CEBPAsingle-mut), are associated with favourable prognosis in the AML patients. However, the reason why CEBPAsingle-mut patients have a poorer outcome than CEBPAdouble-mut patients remains unclear and a comprehensive study to evaluate the biological difference between these two groups is still lacking.
In this study, we investigated the prevalence and clinical relevance of CEBPAdouble-mut and CEBPAsingle-mut and their association with other genetic changes in a large cohort of 543 consecutive de novo AML patients at the National Taiwan University Hospital (NTUH). This study was approved by the Institutional Review Board of NTUH; written informed consents were obtained from all participants in accordance with the Declaration of Helsinki. CEBPA mutations were detected by genomic-DNA PCR and direct sequencing as described earlier (Lin et al, 2005). Mutational analyses of FLT3/ITD, FLT3/TKD N-RAS, K-RAS, NPM1, CEBPA, KIT, AML1 and MLL/PTD were carried out as previously described (Hou et al, 2008).
Among the 543 AML patients recruited, we identified 71 (13.1%) patients with CEBPA mutations, including 47 CEBPAdouble-mut and 24 CEBPAsingle-mut. Compared with patients who have CEBPAdouble-mut, those with CEBPAsingle-mut had lower incidences to express HLA-DR (65 vs 96%, P=0.0014), CD7 (44 vs 79%, P=0.006) and CD15 (35 vs 85%, P<0.0001), but a higher incidence to express CD56 (35 vs 11%, P=0.038) on leukemia cells. Apart from this, there were no differences in other clinical parameters including age, sex, haemogram, LDH level, FAB subtype and karyotype between these two groups. No matter CEBPAsingle-mut or CEBPAdouble-mut, the mutation disappeared at complete remission in all patients who had paired bone marrow samples for analysis and reappeared at relapse.
Patients with CEBPAsingle-mut had a higher incidence of NPM1 mutation than those with CEBPAdouble-mut (4/24, 16.7 vs 0%, P=0.0109). There was also a higher incidence of concurrent mutation of FLT3/ITD, FLT3/TKD, AML1/RUNX1 or MLL/PTD in CEBPAsingle-mut patients than in CEBPAdouble-mut patients (20.8 vs 10.6%, 12.5 vs 4.3%, 8.3 vs 2.1% and 4.2 vs 0%, respectively), but the difference did not reach statistical significance. However, when combined together, simultaneous alteration of any one of these four mutations occurred more frequently in the former group than in the latter (37.5 vs 14.9%, P=0.039). More intriguingly, all four CEBPAsingle-mut patients with NPM1 mutation also simultaneously had FLT3/ITD (2 patients), FLT3/TKD (1 patient), or both (1 patient).
In terms of outcome, CEBPAdouble-mut patients had a higher complete remission rate than CEBPAsingle-mut patients (91 vs 56.3%, P=0.0051). The patients with CEBPAdouble-mut had a significant longer overall survival (OS) than those with CEBPAwild or CEBPAsingle-mut (median: not reached vs 29.8 months and 7.5 months; P=0.013 and P=0.001, respectively; among 3 groups, P=0.007, Figure 1A). The same was also true for disease-free survival (DFS) (median: 59 months vs 8 months and 4 months; P=0.016 and P=0.027, respectively; among 3 groups, P=0.037). Among the subgroup of patients with normal karyotype, the differences in OS and DFS between CEBPAdouble-mut and CEBPAsingle-mut patients were still obvious (P=0.002 and P=0.019, respectively, Figure 1B). The multivariate analysis clearly identified CEBPAdouble-mut, but not CEBPAsingle-mut as an independent prognostic factor for OS and DFS (hazard ratio 0.362, 95% CI 0.182–0.721, P=0.004 and hazard ratio 0.426, 95% CI 0.263–0.691, P=0.001, respectively, Table 1).
From the above findings, we hypothesise that the close association of CEBPAsingle-mut with CD56 expression (Raspadori et al, 2001) and other poor-risk genetic alterations, such as FLT3/ITD, FLT3/TKD, MLL/PTD and AML1/RUNX1, (Schnittger et al, 2000; Harada et al, 2004; Whitman et al, 2008) may partially explain why CEBPAsingle-mut predisposes to inferior outcome than CEBPAdouble-mut. We also observed a trend of shorter OS in CEBPAsingle-mut patients who had concurrent FLT3/ITD, FLT3/TKD,MLL/PTD or AML1/RUNX1 mutation than those who did not (P=0.064, Figure 2).
In summary, about one-third of patients with CEBPA mutations had CEBPAsingle-mut, which were closely associated with CD56 expression but inversely correlated with HLA-DR, CD7 and CD15 expression. Compared with patients who have CEBPAdouble-mut, those with CEBPAsingle-mut had a higher incidence of concurrent FLT3/ITD, FLT3/TKD, MLL/PTD or AML1/RUNX1 mutation and had a poorer prognosis. This study provides evidences independently from previous ones, stressing the differences in biological characteristics between CEBPAsingle-mut and CEBPAdouble-mut AML and their possible prognostic implication. Further studies are necessary to clarify whether the close association of CEBPAsingle-mut with CD56 expression and other poor-risk gene alterations contributes to the poorer outcome of this group of patients.
Conflict of interest
The authors declare no conflict of interest.
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16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
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Hou, HA., Lin, LI., Chen, CY. et al. Reply to ‘Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favorable prognosis’. Br J Cancer 101, 738–740 (2009). https://doi.org/10.1038/sj.bjc.6605207
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DOI: https://doi.org/10.1038/sj.bjc.6605207
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